Poly-adenosine diphosphate (ADP)-ribose (PAR) polymers are the product of post-translational modifications carried out by PAR polymerases (PARPs). PAR is polymerized by PARPs onto acceptor proteins using nicotinamide adenine dinucleotide (NAD+) as substrate (FIG. 1). PAR polymers are localized to distinct cellular structures in different phases of the cell cycle and localize to the mitotic spindle during mitosis (FIG. 2). There are at least 18 PARPs in the human genome: the domain structure for several PARPs is depicted in FIG. 3. However, the specific biological function and protein substrates of these PARPs are not fully characterized (Ame et al., Bioessays 26:882-893, 2004). The identification of the function and the substrates of each member of this family of proteins has been difficult to date.
PAR polymers are required for normal cell division and PARP knockouts in Drosophila melanogaster are embryonic lethal (Tulin et al., Genes Dev. 16:2108-2119, 2002). The concentration, length, and extent of PAR branching are regulated by a balance of activities of the PARPs and PAR glycohydrolase (PARG), a highly specific, processive endo- and exo-glycosidase (Hatakeyama et al., J. Biol. Chem. 261:14902-14911, 1986). Poly-ADP-ribose polymers have generally been implicated for a role in several different human diseases including cancer, ischemic injury, inflammatory diseases, cardiovascular diseases, and neurodegenerative disorders.
We have discovered that several PARP proteins are localized to the nucleus and/or are required for cell cycle progression through mitosis. We have also discovered a role for several PARP proteins in the formation, nucleation, and disassembly of stress granules. Stress granules are distinct cellular structures that form in the cytosol upon exposure of a cell to stress conditions. Stress granules are composed of both proteins and RNA molecules. The RNA molecules present in stress granules are mRNA molecules stalled in translation pre-initiation complexes. Stress granules are typically 100 to 200 nM in size and are commonly associated with the endoplasmic reticulum. Stress granules have been implicated in several different disease states including cardiovascular disorders, inflammatory disorders, neurological disorders, and ischemic-reperfusion injury.
Methods and compositions for the treatment of stress granule-related disorders and cancer are presently desired.